Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma
Open Access
- 24 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (7), 1-14
- https://doi.org/10.1038/s41419-020-02749-7
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal–epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib’s mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.Keywords
This publication has 44 references indexed in Scilit:
- Pathogenesis, Diagnosis, and Management of CholangiocarcinomaGastroenterology, 2013
- MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expressionCarcinogenesis: Integrative Cancer Research, 2013
- Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapiesOncogene, 2013
- Surgical Approach for Long-term Survival of Patients With Intrahepatic CholangiocarcinomaArchives of Surgery, 2012
- Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency, Implicating Wnt SignalingNeuron, 2011
- PI3K/AKT/mTOR Pathway in AngiogenesisFrontiers in Molecular Neuroscience, 2011
- CD24 Is a Novel Predictor for Poor Prognosis of Hepatocellular Carcinoma after SurgeryClinical Cancer Research, 2009
- p21 in cancer: intricate networks and multiple activitiesNature Reviews Cancer, 2009
- Cytokeratin 10 and Cytokeratin 19: Predictive Markers for Poor Prognosis in Hepatocellular Carcinoma Patients after Curative ResectionClinical Cancer Research, 2008
- Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentialsZeitschrift für Krebsforschung und Klinische Onkologie, 2008